Dietary lemon alleviates hypercholesterolemia by elevating acetylcarnitine and activating CYP7A1-dependent bile acid synthesis

Abstract Lemon ( Citrus limon ) is a flavonoid-rich citrus fruit with potential lipid-lowering properties, but the mechanisms underlying these effects remain poorly understood. We evaluated lemon powder in mice fed a high-fat diet and investigated candidate mediators using metabolomics and hepatocyte experiments. Lemon powder reduced serum total cholesterol and low-density lipoprotein cholesterol, lowered hepatic cholesterol, and increased circulating acetylcarnitine and hepatic CRAT expression. Acetylcarnitine administration lowered cholesterol in mice with established diet-induced hypercholesterolemia and reduced lipid accumulation in fatty acid-treated HepG2 cells. Lemon powder increased hepatic cholesterol 7α-hydroxylase (CYP7A1) expression and fecal total bile acid levels; acetylcarnitine also increased hepatic CYP7A1. In HepG2 cells, CYP7A1 knockdown attenuated acetylcarnitine-induced cholesterol lowering. These findings identify acetylcarnitine as a candidate mediator of the response to lemon powder and support further evaluation of lemon-based dietary interventions.